In last month’s issue of Nature Reviews Drug Discovery, György Keserü of Gedeon Richter and Gergely Makara of Merck published a thought-provoking analysis of recent trends in lead discovery. Their results illustrate the potential of fragment-based methods, but also point out the still sizable gap from current practice.
The authors assembled a database of 335 hit-lead pairs derived from high-throughput screening (HTS) that were published between 2000 and 2007. They also assembled a database of 84 non-HTS hit-lead pairs published between 2000 and February 2008, consisting of fragment-based, virtual screening, natural product, and miscellaneous examples. They then compared properties – such as potency, molecular mass, logP, logS (a calculated measure of solubility), and ligand efficiency – of the initial hits with the resulting leads.
The results for HTS hits are not pretty: the lipophilicity as assessed by logP was considerably higher on average for HTS hits than for hits from any other methods, and this only increased as the hits were progressed to leads. The same goes for (in)solubility (as measured by logS). Even more alarming, the average properties of even the hits are worse than those of a collection of 541 approved drugs.
Fragment hits start out with the lowest lipophilicity and highest predicted solubility, but during hit-to-lead optimization these properties deteriorate to the point where they are similar on average to leads derived from HTS. Also surprisingly, the ligand efficiency of fragment hits and leads are, if anything, lower than their HTS counterparts, contrary to expectations. Even the average molecular weight of fragment-derived leads is not much lower than HTS-derived leads.
So what’s going wrong? The authors point out that, at most larger companies, fragment-based approaches are often only attempted after HTS has failed, suggesting that the targets tackled by fragment-based methods may be inherently more difficult. But they also suggest that in the early stages of hit-to-lead optimization the primary measure of success is how many compounds are delivered to lead optimization, which could encourage rapid hit expansion with simple chemistries to rapidly boost potency by adding grease, leading to more hydrophobic, less soluble molecules that will ultimately struggle in the clinic.
The authors suggest a new metric, ligand-efficiency-dependent lipophilicity, or LELP, to help avoid this trap:
LELP = (log P / LE)
Since a desirable logP range is between 0 and 3, and a desirable ligand efficiency is above 0.4, one should strive for LELP values between 0 and 7.5. There are already lots of metrics out there for evaluating molecules: see, for example, discussions of %LE, antibacterial efficiency, and fit quality (also here and here). Is a new one really necessary? Perhaps, if it gets people to focus on non-lipophilic means of increasing potency.
The authors end on a positive note for fragments:
Bearing in mind the sampling of chemical space, hit properties and synthetic accessibility, we consider that fragment hits are the optimum starting points for lead discovery and optimization.
There is, however, a burden on the team transforming a fragment hit into a viable lead: it is important to focus not merely on improving potency, but on maintaining as many of the fragment-like properties that make fragments attractive starting points in the first place. Although this goes without saying, analyses like this one suggest that it still needs to be said – and heard.